Premature atherosclerosis is the major cause of morbidity and mortality in both types 1 and 2 diabetes. The overall objective of this Program Project is to better understand biochemical and molecular mechanisms involved in the pathogenesis of diabetic macrovascular disease. The program project is comprised of 4 inter-related projects and 3 cores. Project 1 will study the the role of an inflammatory molecule, serum amyloid A (SAA) in mediating the interaction of atherogenic lipoproteins with the vascular wall, thereby enhancing atherosclerosis. It will investigate how SAA alters the interaction of lipoproteins with extracellular vascular matrix molecules and alters cellular lipid metabolism and endothelial activation providing insight into the link between inflammation and atherosclerosis in diabetes. Project 2 is aimed at understanding the role of fatty acyl-CoA synthesis in the initiation of atherosclerosis in diabetes. Acyl-CoA synthesis is increased in diabetes. The effect of modulation of acyl-CoA synthesis in endothelial cells and macrophages on lesion initiation and inflammation is the focus of this project. Project 3 will study the role of diabetes on the regulation of reverse cholesterol transport, a process that plays a critical role in atherogenesis. The effect of diabetes on transporters that play critical roles in removing excess lipids from cells will be studied in this project. Project 4 will study biochemical pathways involved in glycation and glycoxidation reactions that play a role in damaging HDL, thereby accelerating atherosclerosis in diabetes. This project will also assess how the diabetic milieu alters HDL's protein composition and its anti-inflammatory properties. Diabetes-mediated alterations in HDL composition and function could impair HDL's atheroprotective functions and accelerate atherosclerosis in diabetes. These projects will be supported by an administrative and 2 scientific cores: The Mouse and Tisssue Core will provide the projects with mice and histochemical and immunohistochemical evaluation of tissues from several mouse models of diabetes. The Mass Spectrometry Core will provide sophisticated biochemical support for the in vitro and in vivo studies proposed in all the projects. The increased understanding of the pathogenesis of the premature vascular disease in diabetes that will be derived has important therapeutic implications for the prevention and treatment of macrovascular disease in diabetes.